Cortex-sparing damage to the corticospinal tract, a possible outcome in cases of subcortical stroke or multiple sclerosis, can result in severe hemiparesis or hemiplegia. When the damage is complete, the prognosis for rehabilitation is extremely poor. In these cases, cortical reorganization of the affected hemisphere is unlikely to result in motor recovery given that the descending corticofugal fibers have been destroyed. And while transfer of motor representation to the non-affected hemisphere may be the most viable route to motor rehabilitation for such patients, such a transfer is likely to be limited by the persistence of interhemispheric inhibition (IHI) from the spared cortex of the affected side upon the contralesional hemispheric cortex. In the normal state, these connections are thought to suppress the latent motor representation of each hemisphere over the ipsilateral hemibody. The goal of this line of research is to develop a neuromodulation-based treatment approach to disrupt this suppressive effect, leading to disinhibition of the contralesional hemisphere's latent potential for motor control over the affected hemibody and enhance motor recovery. Experimentation will be carried out in two specific aims. Our approach involves the use of chronic, electrical stimulation of the corpus callosum to modulate interhemispheric communication and functionally disrupt on-going IHI. In specific aim 1, the goal is to determine the effect of chronic stimulation of the corpus callosum on motor recovery in a primate model of complete corticospinal/internal capsule lesion. Following placement of the corpus callosum stimulation electrode and a cephalic recording chamber, the internal capsule will be mapped unilaterally and ablated with electrodes placed through the chamber. The completeness of the lesion will be confirmed using motor evoked potentials derived from transcranial magnetic stimulation. Following three months of natural recovery, two three-month treatment blocks will take place with animals assigned to receive treatment during one of the two blocks and sham treatment in the other block. Motor function will be monitored using the modified Brinkman board as the primary outcome measure. In aim 2, we will determine whether chronic stimulation of the corpus callosum is associated with changes in motor representation of the contralesional motor cortex. We expect that chronic corpus callosum stimulation will lead the contralesional hemisphere to acquire motor representation and control over the affected side of the body. The preliminary data acquired from the proposed experimentation will be used for a subsequent pre-clinical application. PUBLIC HEALTH RELEVANCE: The goal of this study is to determine whether electrical stimulation of certain brain regions can be used to improve recovery in patients with motor deficits following stroke or other types of brain damage. In some cases of subcortical stroke, a type of stroke where the damage occurs deep in the brain, there is limited opportunity for recovery as the fibers that connect the brain to the body have been destroyed. There is evidence that the opposite side of the brain may have a latent ability to assume motor function over the side of the body that is impaired, however this ability is limited by on-going interactions that occur between the two sides of the brain by way of the corpus callosum. To address this, we propose to disrupt this communication between the two sides of the brain by electrically stimulating the corpus callosum in an animal model of stroke. The effect of stimulation on both motor recovery and the motor representation of the side of the body affected by the stroke will be monitored over time. New treatments that can further enhance recovery of function after strokes are necessary and, if proven efficacious, will have a dramatic impact given the combined high incidence and prevalence of neurological deficits and the high economic cost from stroke in the general population.